Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system myelin that afflicts well over 2 million people in the Western world (Cassan, C., and R. S. Liblau. 2007. Immune tolerance and control of CNS autoimmunity: from animal models to MS patients. J Neurochem 100:883-892; McFarland, H. F., and R. Martin. 2007. Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8:913-919; and Hauser, S. L., and J. R. Oksenberg. 2006. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron 52:61-76). Although the etiology of MS is currently unknown, substantial evidence indicates that autoimmune responses may be a factor for initiation and progression of the disease. Interferon-beta (IFN-β) is currently used as a mainstream therapy for MS (Javed, A., and A. T. Reder. 2006. Therapeutic role of beta-interferons in multiple sclerosis. Pharmacol Ther 110:35-56; Borden, E. C., G. C. Sen, G. Uze, R H. Silverman, R. M. Ransohoff, G. R. Foster, and G. R. Stark. 2007. Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov 6:975-990; and Tourbah, A., and O. Lyon-Caen. 2007. Interferons in multiple sclerosis: ten years' experience. Biochimie 89:899-902). IFN-β is considered a disease-modifying treatment that can reduce subclinical disease measured by magnetic resonance imaging (MRI) although the clinical benefit reflects an approximate 30% reduction in the attack rate.
Aside from the modest efficacy of IFN-β, the drug has disadvantages including high costs and substantial inter-patient variability in tolerability and efficacy. Also, IFN-β most likely inhibits MS through modulation of general regulatory pathways rather than by specifically disabling pathogenic clonotypes. Because IFN-β generally inhibits autoimmune responses without causing immunological tolerance, IFN-β is typically chronically self-administered as an injection for a lifetime.
Experimental autoimmune encephalomyelitis (EAE) is a widely studied animal model of MS and has helped to shape the current understanding of the pathophysiology of MS (Gold, R., C. Linington, and H. Lassmann. 2006. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129:1953-1971). Like MS, EAE is inhibited by administration of IFN-β. A substantial number of studies have shown that Type I interferons effectively inhibit EAE or experimental autoimmune neuritis when interferon-α/β is administered post-immunization during the induction or effector phases of disease (Abreu, S. L. 1982. Suppression of experimental allergic encephalomyelitis by interferon. Immunol Commun 11:1-7; Hertz, F., and R. Deghenghi. 1985. Effect of rat and beta-human interferons on hyperacute experimental allergic encephalomyelitis in rats. Agents Actions 16:397-403; Brod, S. A., M. Khan, R. H. Kerman, and M. Pappolla. 1995. Oral administration of human or murine interferon alpha suppresses relapses and modifies adoptive transfer in experimental autoimmune encephalomyelitis. J Neuroimmunol 58:61-69; Brod, S. A., M. Scott, D. K. Burns, and J. T. Phillips. 1995. Modification of acute experimental autoimmune encephalomyelitis in the Lewis rat by oral administration of type 1 interferons. J Interferon Cytokine Res 15:115-122; Yu, M., A. Nishiyama, B. D. Trapp, and V. K. Tuohy. 1996. Interferon-beta inhibits progression of relapsing-remitting experimental autoimmune encephalomyelitis. J Neuroimmunol 64:91-100; Brod, S. A., and M. Khan. 1996. Oral administration of IFN-alpha is superior to subcutaneous administration of IFN-alpha in the suppression of chronic relapsing experimental autoimmune encephalomyelitis. J Autoimmun 9:11-20; Vriesendorp, F. J., R. E. Flynn, M. Khan, M. A. Pappolla, and S. A. Brod. 1996. Oral administration of type I interferon modulates the course of experimental allergic neuritis. Autoimmunity 24:157-165; Yasuda, C. L., A. Al-Sabbagh, E. C. Oliveira, B. M. Diaz-Bardales, A. A. Garcia, and L. M. Santos. 1999. Interferon beta modulates experimental autoimmune encephalomyelitis by altering the pattern of cytokine secretion. Immunol Invest 28:115-126; Zou, L. P., D. H. Ma, L. Wei, P. H. van der Meide, E. Mix, and J. Zhu. 1999. IFN-beta suppresses experimental autoimmune neuritis in Lewis rats by inhibiting the migration of inflammatory cells into peripheral nervous tissue. J Neurosci Res 56:123-130; Tuohy, V. K., M. Yu, L. Yin, P. M. Mathisen, J. M. Johnson, and J. A. Kawczak. 2000. Modulation of the IL-10/IL-12 cytokine circuit by interferon-beta inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis. J Neuroimmunol 111:55-63; and Floris, S., S. R. Ruuls, A. Wierinckx, S. M. van der Pol, E. Dopp, P. H. van der Meide, C. D. Dijkstra, and H. E. De Vries. 2002. Interferon-beta directly influences monocyte infiltration into the central nervous system. J Neuroimmunol 127:69-79).
The inhibitory mechanism of IFN-β is associated with altered immunoregulation, but no evidence exists to indicate that IFN-β causes an antigen-specific immunological tolerance. Endogenous IFN-β also appears to limit encephalitogenic responses where EAE is exaggerated in mice genetically deficient in IFN-β (Teige, I., A. Treschow, A. Teige, R. Mattsson, V. Navikas, T. Leanderson, R. Holmdahl, and S. Issazadeh-Navikas. 2003. IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis. J Immunol 170:4776-4784, Teige, I., Y. Liu, and S. Issazadeh-Navikas. 2006. IFN-beta inhibits T cell activation capacity of central nervous system APCs. J Immunol 177:3542-3553) or the type I IFN receptor (Prinz, M., H. Schmidt, A. Mildner, K. P. Knobeloch, U. K. Hanisch, J. Raasch, D. Merkler, C. Detje, I. Gutcher, J. Mages, R. Lang, R. Martin, R. Gold, B. Becher, W. Bruck, and U. Kalinke. 2008. Distinct and Nonredundant In Vivo Functions of IFNAR on Myeloid Cells Limit Autoimmunity in the Central Nervous System. Immunity). Indeed, expression of the type I IFN receptor on myeloid cells appears to be a factor in the mechanism by which IFN-β controls encephalitogenic responses.
Antigen-specific therapies may be considered advantageous compared to general immunosuppressive strategies at least because the former has potential to cause specific immunological tolerance (Faria, A. M., and H. L. Weiner. 2006. Oral tolerance: therapeutic implications for autoimmune diseases. Clin Dev Immunol 13:143-157; Fontoura, P., H. Garren, and L. Steinman. 2005. Antigen-specific therapies in multiple sclerosis: going beyond proteins and peptides. Int Rev Immunol 24:415-446; and Sospedra, M., and R. Martin. 2005. Antigen-specific therapies in multiple sclerosis. Int Rev Immunol 24:393-413). Several antigen-specific therapies are being developed, including those based on altered peptide ligands, DNA vaccines, and mucosal antigen delivery.
Cytokine-antigen fusion proteins were originally developed for vaccination against cancer and infectious agents but have also been explored as tolerogenic vaccines based on the use of inhibitory, anti-inflammatory, or tolerogenic cytokines as the cytokine fusion partner (Mannie, M. D., and D. J. Abbott. 2007a. A fusion protein consisting of IL-16 and the encephalitogenic peptide of myelin basic protein constitutes an antigen-specific tolerogenic vaccine that inhibits experimental autoimmune encephalomyelitis. J Immunol 179:1458-1465 and Mannie, M. D., B. A. Clayson, E. J. Buskirk, J. L. DeVine, J. J. Hernandez, and D. J. Abbott. 2007b. IL-2/neuroantigen fusion proteins as antigen-specific tolerogens in experimental autoimmune encephalomyelitis (EAE): correlation of T cell-mediated antigen presentation and tolerance induction. J Immunol 178:2835-2843). Two cytokine-antigen fusion proteins in which the IL-2 or IL-16 cytokines were fused to the encephalitogenic determinant of MBP (i.e., IL2-NAg or NAg-IL16) have successfully been used to prevent a subsequent encephalitogenic sensitization and to treat ongoing EAE (WO 2008/13082).
However, it remains desirable to have additional antigen-specific therapies for the treatment of immunological disorders.